title: Potent inhibition of DOT1L as treatment of MLL-fusion leukemia.
abstract: Rearrangements of the MLL gene define a genetically distinct subset of acute leukemias with poor prognosis. Current treatment options are of limited effectiveness; thus, there is a pressing need for new therapies for this disease. Genetic and small molecule inhibitor studies have demonstrated that the histone methyltransferase DOT1L is required for the development and maintenance of MLL-rearranged leukemia in model systems. Here we describe the characterization of EPZ-5676, a potent and selective aminonucleoside inhibitor of DOT1L histone methyltransferase activity. The compound has an inhibition constant value of 80 pM, and demonstrates 37 000-fold selectivity over all other methyltransferases tested. In cellular studies, EPZ-5676 inhibited H3K79 methylation and MLL-fusion target gene expression and demonstrated potent cell killing that was selective for acute leukemia lines bearing MLL translocations. Continuous IV infusion of EPZ-5676 in a rat xenograft model of MLL-rearranged leukemia caused complete tumor regressions that were sustained well beyond the compound infusion period with no significant weight loss or signs of toxicity. EPZ-5676 is therefore a potential treatment of MLL-rearranged leukemia and is under clinical investigation.
authors.affiliation: Epizyme, Inc., 400 Technology Square, Cambridge, MA 02139, USA.
authors.forename: Scott R
authors.initials: SR
authors.lastname: Daigle
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Olhava
authors.forename: Carly A
authors.initials: CA
authors.lastname: Therkelsen
authors.forename: Aravind
authors.initials: A
authors.lastname: Basavapathruni
authors.forename: Lei
authors.initials: L
authors.lastname: Jin
authors.forename: P Ann
authors.initials: PA
authors.lastname: Boriack-Sjodin
authors.forename: Christina J
authors.initials: CJ
authors.lastname: Allain
authors.forename: Christine R
authors.initials: CR
authors.lastname: Klaus
authors.forename: Alejandra
authors.initials: A
authors.lastname: Raimondi
authors.forename: Margaret Porter
authors.initials: MP
authors.lastname: Scott
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Waters
authors.forename: Richard
authors.initials: R
authors.lastname: Chesworth
authors.forename: Mikel P
authors.initials: MP
authors.lastname: Moyer
authors.forename: Robert A
authors.initials: RA
authors.lastname: Copeland
authors.forename: Victoria M
authors.initials: VM
authors.lastname: Richon
authors.forename: Roy M
authors.initials: RM
authors.lastname: Pollock
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019175:DNA Methylation; D004305:Dose-Response Relationship, Drug; D005260:Female; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors*; D006657:Histones / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000235:genetics* / Q000628:therapy*; D008780:Methyltransferases / Q000037:antagonists & inhibitors*; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D009368:Neoplasm Transplantation; D011487:Protein Conformation; D051381:Rats; D011923:Rats, Nude
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; C583893:EPZ-5676; D006657:Histones; D051788:Myeloid-Lymphoid Leukemia Protein; C473477:DOT1L protein, human; D000076983:Histone Methyltransferases; D008780:Methyltransferases; C583894:DOT1L protein, rat; D011495:Histone-Lysine N-Methyltransferase